DESCRIPTION (taken from application) Alagille syndrome (syndromic bile duct paucity) is a dominant genetic disorder affecting the liver, heart, eye, vertebrae and facial structures. Expressivity is highly variable and penetrance is incomplete, making accurate diagnosis and genetic counseling difficult. The disease gene for Alagille syndrome has been localized to the short arm of chromosome 20 based on linkage analysis and the identification of affected individuals with deletions or translocations involving this region. This proposal builds on the candidate's initial work in establishing reagents from within the Alagille syndrome critical region on chromosome 20, identifying patients with deletions or other rearrangements of this critical region, and redefining the boundaries of the critical region. The aim of this proposal is to use these reagents to identify genes that map within this region. Techniques for identifying expressed sequences that will be focused on in this proposal include cDNA selection and use of the puffer fish (Fugu rubripes) syntenic region to identify conserved sequences. This proposal outlines a five year training program which will allow the candidate to develop into an independent physician scientist. The program will couple didactic efforts with an intensive hands-on laboratory experience. Relevant graduate level courses in molecular and developmental biology will be attended during the first two years of the training period, in addition to laboratory conferences and journal clubs. The initial laboratory experience will provide for a broader exposure to molecular genetic techniques that will be applicable not only to the completion of this proposal but also to subsequent investigations in molecular genetics and developmental biology. This project takes advantage of a multidisciplinary group at The Children's Hospital of Philadelphia, that has identified and begun to study, at the clinical and molecular levels, the largest cohort of Alagille patients in North America, providing an excellent opportunity to study both the clinical expression and molecular basis of this disorder. Identification of the disease gene for Alagille syndrome will lead to a comprehensive genotype-phenotype correlation. Future studies will elucidate the function of this gene and its interactions with other molecules to shed light on an important developmental pathway, the disruption of which results in a disorder with a wide spectrum of clinical manifestation.